The present invention is directed to a hemiphosphate hemihydrate salt of 2-(1-pentyl-3-guanidino)-4-(2-methyl-4-imidazolyl)thiazole having advantageous properties.
U.S. Pat. No. 4,560,690 which is herein incorporated by reference, describes 2-(1-pentyl-3-guanidino)-4-(2-methyl-4-imidazolyl)thiazole and analogs as having antiulcer activity. The form of this preferred compound, reported in said patent is the anhydrous dihydrobromide salt, which is noncrystalline, difficult to purify and possesses properties which are generally less suitable for formulation and use as a medicinal agent in mammals.
International Application No. PCT/US86/02308 (now U.S. Pat. No. 4,997,981), herein incorporated by reference, reports a further improvement in salts of this preferred antiulcer agent and describes the preparation and properties of the dihydrochloride trihydrate salt.
Formulations are generally required in the administration of medicinal agents for a variety of reasons, including taste improvement, accurate delivery, safety (i.e. protection of non-targeted organs and the facilitation of the manufacture of the dosage forms. In the preparation of a dosage form, therefore, various excipients are added to obtain a dosage form that is suitable for administration. When the administration route is to be oral, it is often desirable to add sweeteners, flavorants, taste-maskers, binders, plasticizers, lubricants, swelling matrices, disintegrants, wetting agents and the like. These excipients facilitate manufacture and help to improve patient compliance.
Patient compliance is an important factor in the self-administration of orally-administered medicinal agents, and can be low when the patient is requested to self-administer multiple tablets, overlarge tablets or tablets which exhibit disagreeable flavor characteristics. Many patients experience either psychological (e.g., anxiety) or physiological (e.g., gag reflex) problems when attempting to self-administer medicinal agents. Thus it can be of great benefit to reduce the number of tablets necessary and to reduce the size of said tablets in an effort to improve patient compliance.
Therefore it is necessary to minimize the amount of excipients utilized to keep the dosage size small. The amounts of the various excipients used are therefore limited by the size of the dosage form and by the amount of drug substance in the dosage form. As the dose of the drug increases, the formulator is allowed less excipient with which to modify the properties of the drug powder. Once the drug powder dominates the dosage form at concentrations above 50%, the excipients may become less effective. This could necessitate the division of the dose into two or more tablets or capsules, which as mentioned hereinabove is not pharmacologically desirable. An attractive alternative to dividing the dose in such a manner is to increase the potency of the active ingredient. Increased potency can be achieved by reducing the molecular weight of the active agent being used thereby resulting in a lower mass of active agent being necessary to achieve the desired activity. When high molecular weight salts are utilized in the preparation of the formulation, as is often necessary to achieve the proper characteristics of stability and crystallinity, the potency can be improved by the substitution of lower molecular weight salt forms.
It is the object of this invention, therefore, to provide a more potent form of 2-(1-pentyl-3-guanidino)-4-(2-methyl-4-imidazolyl)thiazole, namely the hemiphosphate hemihydrate salt thereof.